Piperidine, tetrahydropyridine and piperazine derivatives, their preparation and use

ABSTRACT

A piperidine, tetrahydropyridine or piperazine derivative having formula (I),  
                 
 
     any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein B is C 1-10 -alkylene, C 1-10 -alkenylene or C 1-10 -alkynylene; X is —O—, —S—, or CR 4 R 5 —; and Y is —CR 6 R 7 , —CR 6 R 7 —CR 8 R 9 , or CR 6 ═CR 7 —; or X and Y together form a group —CR 4 ═CR 5 , or —CR 4 —CR 5 —CR 6 R 7− ; Z is —O—, or —S—; W is N, C, or CH, and the dotted line is an optional bond; A is a bicyclic ring selected from (Ia) or (Ib) wherein E 1 , E 2  and E 3  are selected from O, S, N, NR 11 , C, CR 12  and CHR 13 , and the dotted line indicates an optional bond, provided that E 2  and E 1  and/or E 3  may not simultaneously be O, or S. The compounds of the invention are considered useful for the treatment of affective disorders, such as depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder, obsessive compulsive disorder, and eating disorders.

[0001] The present invention relates to novel piperidine,tetrahydropyridine and piperazine derivatives which are potent serotoninreuptake inhibitors, pharmaceutical compositions containing thesecompounds and the use thereof for the treatment of disorders or diseasesresponsive to the inhibition of serotonin re-uptake. The compounds ofthe invention also possess antagonistic activity at 5-HT_(1A) receptorsand are considered to be particularly useful for the treatment ofdepression.

BACKGROUND

[0002] Selective serotonin (or 5-HT) reuptake inhibitors (SSRIs) such asfluoxetine, paroxetine, sertraline, fluvoxamine and citalopram representa major step forward in the treatment of depression because they havefewer and less severe side effects compared to first generationantidepressant (tricyclics and non-selective MAO inhibitors). The sideeffects associated with first generation antidepressants are such thatthey cause some patients to withdraw from treatment.

[0003] SSRIs and all other antidepressants currently available sufferfrom a serious drawback in that several weeks of treatment are necessaryto produce the therapeutic effect. The late onset of action is asignificant problem, particularly in the treatment of patients withsevere depression and suicide potential. Further, one in three patientsare not responsive to SSRIs.

[0004] Electrophysiological experiments in rats have shown that acuteadministration of SSRIs reduces firing of 5-HT neurons of dorsal raphenucleus in the rodent brain, whereas sustained treatment with SSRIsleads to normalization of the firing activity of the 5-HT neurons(Arborelius, L. et al, Naunyn-Schmiedeberg's Arch. Pharmacol. 1995, 352,157; Gartside. S. E. et al Br. J. Pharmacol. 1995, 115. 1064: Chaput. Y.et al. Naunvi-Schmiedeberg s Arch. Pharmacol. 1986, 33, 342).

[0005] Further, it has been shown that the recovery of the firingactivity of 5-HT neurons is linked to desensitization of somatodendritic5-HT_(1A) autoreceptors (Le Poul, E. et al, Naunyn-Schrniedeberg's Arch.Pharmacol. 1995, 352, 141; Invemizzi, R. et at, Eur. J. Pharmacol. 1994,260, 243).

[0006] It has thus been suggested that simultaneous administration ofSSRls and an agent causing rapid desensitization or inhibition of the5-HT_(1A) receptor mediated feed back mechanism would lead to rapidonset of antidepressive effect (Artigas, F. et al, Trends Nveurosci.1996, 19, 378; De Vry, J., et al, Drug News Perspec. 1996, 9, 270).

[0007] The effect of combined administration of a compound that inhibitsserotonin reuptake and a 5-HT_(1A) receptor antagonist has beenevaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol.,1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, pa 064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). Inthese studies it was a found that 5-HT_(1A) receptor antagonists inhibitthe decrease in firing caused by acute administration of serotoninreuptake inhibitors.

[0008] Further, treatment with a combination of pindolol (a well known⁵-HT_(1A) receptor and β-adrenoceptor antagonist) and SSRIs has beenevaluated in clinical trials. A remarkable improvement of the mood ofpatients was reported within one week. In addition, combinedadministration of pindolol and an SSRI was shown to have a good effecton patients who were non-responsive to treatment with currentlyavailable antidepressants (Artigas F. et al., Arch. Gen. Psychiatry,1994, 51, p 248-251 and Blier, P. et al., J. Clin. Psychopharinacol.1995, 15, p 217-222).

[0009] Several patent applications have been filed which cover the useof a combination of a 5-HT_(1A) antagonist and a serotonin reuptakeinhibitor for the treatment of depression (see EP-A2-687 472 andEP-A2-714 663).

[0010] In EP-A1-529 462, certain 1,4-benzodioxan derivatives having thegeneral formula

[0011] wherein B is an optionally substituted indol-3-yl group and Q isC_(n)H_(2n), wherein n is 1, 2, 3, 4, 5, or 6 are disclosed. Thesecompounds are said to have serotonin agonistic and serotoninantagonistic activity as well as serotonin reuptake inhibiting activityand to be useful as anxiolytics, antidepressants, antipsychotics,antihypertensives, and cerebroprotective agents.

[0012] In U.S. Pat. No. 5,002,948, Perregaard et al. disclose relatedindoles, indazoles, 2-indolones and 2,3-dihydro derivatives thereofhaving the formula

[0013] wherein X is —CH—, —CH₂—, —NH—, or —CO—; and Ar is

[0014] wherein Y is O, or S, Z is O, S, or —CH₂—, and n is 1,2, or 3.

[0015] These compounds are valuable 5-HT_(1A) receptor ligands.

OBJECT OF THE INVENTION

[0016] It is the object of the present invention to provide compoundswith potent serotonin reuptake inhibiting activity as well asantagonistic properties at 5-HT_(1A) receptors. Such compounds may beuseful as fast onset of action medicaments for the treatment ofaffective disorders, such as depression, psychosis, anxiety disordersincluding general anxiety disorder, panic disorder, obsessive compulsivedisorder, and eating disorders.

[0017] A further object of the present invention is to provide apharmaceutical composition comprising the above compounds as activeingredients.

SUMMARY OF THE INVENTION

[0018] The invention then, inter alia, comprises the following alone orin combination:

[0019] A pipenrdine, tetrahydropyridine or piperazine derivative havingthe formula:

[0020] any of its enantiomers or any mixture thereof, or an acidaddition salt thereof,

[0021] wherein

[0022] B is C₁₋₁₀-alkylene, C₂₋₁₀-alkenylene or C₂₋₁₀-alkynylene;

[0023] X is —O—, —S—, or —CR⁴R⁵—; and

[0024] Y is —CR⁶R⁷—, —CR⁶═R⁷—CR⁸R⁹—, or —CR⁶CR⁷—; or

[0025] X and Y together form a group —CR⁴═CR⁵—, or —CR⁴═CR⁵—CR⁶R⁷—; p2 Zis —O—, or —S—;

[0026] W is N, C, or CH, and the dotted line is an optional bond;

[0027] R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected fromhydrogen, halogen, trifluoromethyl, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkoxy,

[0028] C₁₋₆-alkylthio, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,phenylamnino or phenyl-C₁₋₆-alkylamino wherein the phenyl group may besubstituted, acylamino, hydroxy, —SH, cyano, nitro, —COOR¹⁸, —SO₂—R¹⁹and

[0029] C₁₋₆-alkyl substituted with a substituent selected from halogen,C₁₋₆-alkoxy, C₁₋₆-alkylthio, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,acylamino, hydroxy, —SH, cyano. nitro, —COOR¹⁸ and —SO—R¹⁹;

[0030] R¹⁸ is hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, phenylor phenyl-C₁₋₆ alkyl wherein the phenyl groups may be substituted,amino, C₁₋₆-alkylamino or C₁₋₆-dialkyamino, and

[0031] R¹⁹ is C₁₋₆-alkyl, amino, C₁₋₆alkylamino, C₁₋₆-dialkylamino,phenyl or phenyl-C₁₋₆-alkyl wherein the phenyl groups may besubstituted;

[0032] A is a bicyclic ring selected from

[0033]  wherein E¹, E² and E³ are selected from O, S, N, NR¹¹, C, CR¹²and CHR¹³, and the dotted line indicates an optional bond, provided thatE² and E¹ and/or E³ may not simultaneously be O, or S;

[0034] R¹, R², R³, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are eachindependently selected from hydrogen, halogen, trifluoromethyl,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy, formyl, acyl, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, acylarmino,

[0035] C₁₋₆-alkoxycarbonylarnino, aminocarbonylamino,C₁₋₆-alkylaminocarbonylamino, C₁₋₆-dialkylaminocarbonylamino, nitro,cyano and —SO₂—R¹⁹, wherein R¹⁹ is C₁₋₆-alkyl, amino,

[0036] C₁₋₆-alkylamino, C₁₋₆-dialkylamino, phenyl, or phenyl-C₁₋₆-alkylwherein the phenyl groups may be substituted;

[0037] R¹¹ is selected from hydrogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂-alkynyl, C₃₋₇-cycloaflyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, phenyl orphenyl-C₁₋₆-alkyl wherein the phenyl group may be substituted, acyl,fonnyl and —SO₂—R¹⁹, wherein R¹⁹ is C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, phenyl or phenyl-C₁₋₆-alkyl wherein the phenyl groupsmay be substituted;

[0038] provided that at least one of R⁴-R⁹ is different from hydrogenwhen A is a group of formula (If)

[0039] In one embodiment, the present invention relates to a compoundwherein A is selected from the groups of formula (Ic), (Id) and (Ie)

[0040] wherein E¹, E², E³, and R¹⁴, R¹³, R¹⁶ and R¹⁷ are as defined inclaim 1 and E⁵ is N, C or CR¹² .

[0041] In a further embodiment, the present invention relates to acomnpound wherein the bicyclic ring A is selected from the groups (If)to (Iq):

[0042] which is attached to the remainder of the compound of formula (1)via a carbon atom or a nitrogen atom in any of the two rings and

[0043] wherein the dotted line is an optional bond, E⁶ is O or S, andwherein any of the carbon atoms in the ring may be substituted with anyof the substituents defined for R¹²-R¹⁷ above, and wherein the nitrogenatoms in the ring may be substituted with any of the substituentsdefined above for R¹¹.

[0044] In a preferred embodiment, the present invention relates to acompound wherein A is a group of formula (Ih), (Ij) or (Iq).

[0045] In a more preferred embodiment, the present invention relates toa compound wherein A is a group of formula (Ih) wherein E⁶ is O. Suchcompound is preferably attached to the remainder of the derivative offormula (I) via position 3 in the five-membered ring.

[0046] In a further embodiment, the present invention relates to acompound wherein A is a group of formula (If).

[0047] In a final embodiment, the present invention relates to acompound wherein

[0048] B is C₁₋₆-alkylene, C₂₋₆-alkenylene, or C₂₋₆-alkynylene;

[0049] X is —O—, or —S—; and

[0050] Y is —CR⁶R⁷—, —CR⁶R⁷—CR⁸R⁹—, or —CR⁶═CR⁷; and

[0051] Z is —O—, or —S—;

[0052] W is N, C, or CH;

[0053] R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,halogen, trifluoromethyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,amino, C₁₋₆-alkylamino, C,₆-dialkylamino, phenylamino orphenyl-C₁₋₆-alkylamino wherein the phenyl group may be substituted,hydroxy, cyano, nitro, —COOR¹⁸, —SO, —R¹⁹ and C₁₋₆-alkyl substitutedwith halogen, C₁₋₆-alkoxy, C₁₋₆-alkylthio, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, acylamino, hydroxy, cyano, nitro, —COOR¹⁸ or—SO₂—R¹⁹;

[0054] R¹⁸ is hydrogen, C₁₋₆-alkyl, amino, C₁₋₆-alkylamino orC₁₋₆-dialkylamino;

[0055] R¹⁹ is C₁₋₆-alkyl, amino, C₁₋₆-alkylamino or C₁₋₆-dialkylamino;

[0056] R¹, R², R³, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are eachindependently selected from hydrogen, halogen, trifluoromethyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, nitro and cyano; and

[0057] R¹¹ is selected from hydrogen, C₁₋₆-alkyl, phenyl orphenyl-C₁₋₆-alkyl wherein the phenyl group may be substituted, acyl,formyl and —SO₂—R¹⁹, wherein R¹⁹ is C₁₋₆-alkyl, amino, C₁₋₆-alkylaminoor C, ₆-dialkylamino.

[0058] Specific compounds of the invention are compounds selected from

[0059] 1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,

[0060]1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten4-yl]piperazine,

[0061] 1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,

[0062]1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,

[0063]1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine

[0064]1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,

[0065]1-[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyt]piperazine,

[0066]1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylibenzofuran-3-yl)ethyl]piperazine,

[0067]1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chloronenzofuran-3-yl)ethyl]piperazine,

[0068]1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methvibenzofuran-3-yl)ethyl]piperazine,

[0069] 1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,

[0070]1-[2-(5-Chlorobenzofuran-3-yl)ethyl-]4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyrindine,

[0071]4-[Benzofiuran-7-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,

[0072]1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethyl]piperazine,

[0073]1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)-1-proyl]piperazine,

[0074]1-[8-Cyano-1,4-benzodioxan-5-yl]-4-[3-7-chlorobenzofiuran-3-yl)propyl]piperazine,

[0075]1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine

[0076]1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine

[0077]1-[1,4-Benzodioxan-5-yl]-4-[2-(6-bromobenzofuran-3-yl)ethyl]piperazine,

[0078]1-[1,4-Benzodioxan-5-yl]-4-[3-(4-chlorobenzofuran-3-yl)-1-propyl]piperazine

[0079]1-[1,4-Benzodioxan-5-yl]-4-[4-(4-methylbenzofuran-3-yl)-1-butyl]piperazine

[0080]1-[1,4-Benzodioxan-5-yl]-4-[4-(4-chlorobenzofiuran-3-yl)-1-butyl]piperazine

[0081]1-[1,4-Benzodioxan-5-yl]-4-[4-(7-chlorobenzofuran-3-yl)-1-butyl]piperazine

[0082]4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropy

[0083]4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]piperidine,

[0084]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperazine,

[0085]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperazine

[0086]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]

[0087]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperazine,

[0088]1-[2-Carbamoyl-1,4-benzodioxan-5-yl]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,

[0089]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperazine,

[0090]1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2(6-Chloro-1H-indol-3-yl)ethyl]piperazine,

[0091]1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,

[0092]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(NN-dimethylamino)-1,4-benzodioxan-5-yl]piperazine,

[0093]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]tetrahydropyridine

[0094]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]tetrahydropyridine,

[0095]4-[6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,

[0096]1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,

[0097]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,

[0098]1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,

[0099]1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,

[0100]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]tetrahydropyridine,

[0101] 4-[2(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl1,4-benzodioxa-5-yl]piperidine,

[0102]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2cyano-1,4-benzodioxan-5-yl]piperidine,

[0103]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperidine

[0104]4-[2-(6-Chloro-1H-indol-3-yl]-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperidine,

[0105]1-[2-Carbamoyl-1,4-benzodioxan-5-yl)]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine

[0106]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperidine,

[0107]1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,

[0108]1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-inidol-3-yl)ethyl]piperidine,

[0109]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperidine,

[0110]1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,

[0111]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperazine,

[0112]1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,

[0113]1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,

[0114]1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,

[0115]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]tetrahydropyridine,

[0116]1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,

[0117]1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,

[0118]1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyllpiperidine,

[0119]4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperidine,

[0120]1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,

[0121]1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,or a pharmaceutically acceptable acid addition salt thereof.

[0122] Particularly preferred compounds are

[0123] 1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,

[0124]1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten-4-yl]piperazine,

[0125] 1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4butyl]piperazine,

[0126]1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofaran3-yl)ethyl]piperazine,

[0127]1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,

[0128]1-[Benzofuran-7-yl]4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,

[0129]1-[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyl]piperazine,

[0130]1-1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,

[0131]1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,

[0132]1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,

[0133] 1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,

[0134]1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethyl]piperazine.

[0135]1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofaran-3-yl)-1-propyl]piperazine.

[0136]1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine,

[0137]1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine,and4-[Benzofuran-7yl]-1-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3-tetrahydropyridine,

[0138] or a pharmaceutically acceptable acid addition salt thereof.

[0139] The invention also relates to a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof and at least one pharmaceutically acceptable carrier ordiluent

[0140] In a further embodiment, the invention relates to the use of acompound of formula (I) or a pharmaceutically acceptable acid additionsalt thereof for the preparation of a medicament for the treatment of adisorder or disease responsive to the inhibition of serotonin reuptakeand antagonism of 5-HT_(1A) receptors.

[0141] In particular, the invention relates to the use of a compoundaccording to the invention or a pharmaceutically acceptable acidaddition salt thereof for the preparation of a medicament for thetreatment of affective disorders, such as depression, psychosis, anxietydisorders including general anxiety disorder, panic disorder, obsessivecompulsive disorder, and eating disorders.

[0142] In still another embodiment, the present invention relates to amethod for the treatment of a disorder or disease of living animal body,including a human, which is responsive to the inhibition of serotoninreuptake and antagonism of 5-HT_(1A) receptors comprising administeringto such a living animal body, including a human, a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable acid addition salt thereof.

[0143] In particular, the invention relates to a method for thetreatment of affective disorders, such as depression, psychosis, anxietydisorders including general anxiety disorder, panic disorder, obsessivecompulsive disorder, and eating disorders comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable acid addition salt thereof to a livinganimal body, including a human, in need thereof

[0144] Due to their combined antagonism of ⁵-HT_(1A) receptors andserotonin reuptake inhibiting effect, the compounds of the invention areconsidered particularly useful as fast onset of action medicaments forthe treatment of depression. The compounds may also be useful for thetreatment of depression in patients who are resistant to treatment withcurrently available antidepressants.

[0145] The compounds claimed herein are considered particularly usefulfor the treatment of depression requiring fast onset of antidepressiveeffect, or a depression which is resistant to other antidepressants.

[0146] Halogen means fluoro, chloro, bromo, or iodo.

[0147] C₁₋₆-alkyl means a straight or branched chain of one to sixcarbon atoms, including for example: methyl, ethyl, propyl, isopropyl,butyl, pentyl and hexyl.

[0148] C₂₋₆-alkenyl means a chain of from two to six carbon atomscontaining one double bond, including for example ethenyl,1-,2-propenyl, 2-,3 propenyl etc.

[0149] C₁₋₆-alkynyl means a chain of from two to six carbon atomscontaining one triple bond, including for example ethynyl,1-,2-propynyl, 2-,3-propynyl etc.

[0150] C₁₋₁₀-alkylene means a chain of one to ten carbon atoms,including for example ethylene, propylene, butylene etc. C₁₋₆ alkyleneis an alkylene group as defined above with up to 6 carbon atoms.

[0151] C₂₋₁₀-alkenylene is a chain of two to ten carbon atoms containingone double bond, including for example ethenylene, propenylene,butenylene etc. C₂₋₆ alkenylene is an alkenylene group as defined abovecontaining from 2 to 6 carbon atoms.

[0152] C₂₋₁₀-alkynylene is a chain of from two to ten carbon atomscontaining one triple bond, including for example ethynylene,propynylene, butynylene etc. C₂₋₆ alkynylene is an alkynylene group asdefined above containing from 2 to 6 carbon atoms.

[0153] C₃₋₇-cycloalkyl means cyclic alkyl of from three to seven carbonatoms, including cyclopropyl, cyclobutyl etc.

[0154] C₃₋₇-cycloalkyl-C₁₋₆-alkyl is composed of C₃₋₇-cycloalkyl andC₁₋₆-alkyl wherein C₃₋₇-cycloalkyl and C₁₋₆-alkyl is as defined above.

[0155] C₁₋₆-alkoxy is -O-alkyl where alkyl is as defined above.C₁₋₆-alkylthio is -S-alkyl where alkyl is as defined above.

[0156] Acyl means —CO—C₁₋₆-alkyl wherein C₁₋₆-alkyl is as defined above.

[0157] Amino means NH₂.

[0158] C₁₋₆-alkylamino means —NH—C₁₋₆-alkyl, and C₁₋₆-dialkylamino means—N—(C₁₋₆-alkyl)₂ where C₁₋₆alkly is as defined above.

[0159] C₁₋₆-alhxycarbonylamino means C₁₋₆-alkyl—O—CO—NH— whereinC₁₋₆-alkyl is as defined above.

[0160] C₁₋₆-alkylaminocarbonylamino means C₁₋₆-alkyl-NH—CO—NH— whereinC₁₋₆-alkyl is as defined above.

[0161] C₁₋₆-dialkylaminocarbonylamino means (C₁₋₆-alkyl)₂-NH—CO—NH—wherein C₁₋₄-alkyl is as defined above.

[0162] As used herein a phenyl group which may be substituted means aphenyl group which may be substituted one or more times with asubstituent selected form halogen, trifluoromethyl, cyano, nitro, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, C₁₋₆-alkyl, C₁₋₆-alkoxy and hydroxy.

[0163] Exemplary of organic acid addition salts according to theinvention are those with maleic, fumaric, benzoic, ascorbic, succinic,oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic,acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophyllineacetic acids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of inorganic acid addition saltsaccording to the invention are those with hydrochloric, hydrobromic,sulfuric, sulfarnic, phosphoric, and nitric acids. The acid additionsalts of the invention are preferably pharmaceutically acceptable saltsformed with non-toxic acids.

[0164] Further, the compounds of this invention may exist in unsolvatedas well as in solvated forms with pharmaceutically acceptable solventssuch as water, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

[0165] Some of the compounds of the present invention contain chiralcentres and such compounds exist in the form of isomers (i.e.enantiomers). The invention includes all such isomers and any mixturesthereof including racemic mixtures.

[0166] Racemic forms can be resolved into the optical antipodes by knownmethods, for example, by separation of diastereomeric salts thereof withan optically active acid, and liberating. the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic compounds of the present invention canthus be resolved into their optical antipodes, e.g., by fractionalcrystallization of d- or 1-(tartrates, mandelates, or camphorsulphonate)salts for example. The compounds of the present invention may also beresolved by the formation of diastereomeric derivatives.

[0167] Additional methods for the resolution of optical isomers, knownto those skilled in the art, may be used. Such methods include thosediscussed by J. Jaques, A. Collet, and S. Wilen in “Enantiomers,Racemates, and Resolutions”, John Wiley and Sons, New York (1981).

[0168] Optically active compounds can also be prepared from opticallyactive starting matenals.

[0169] The compounds of the invention can be prepared by one of thefollowing methods comprising:

[0170] a) reducing the carbonyl groups of a compound of formula

[0171]  wherein A, R¹-R³, X, Y, Z, W, and the dotted line are as definedabove;

[0172] b) alkylating an amine of formula

[0173]  wherein R¹-R³, X, Y, Z, W, and the dotted line are as definedabove with a reagent of formula L-B-A wherein A and B are as definedabove and L is a suitable leaving group such as halogen, mesylate, ortosylate;

[0174] c) reductive alkylation of an amine of formula

[0175]  wherein R¹-R³, X, Y, Z, W, and the dotted hine are as definedabove with a reagent of formula K-B′-A, wherein A is as defined above, Kis either an aldehyde or a carboxylic acid group and B′ is such a group,that —CH₂-B′— belongs to the groups defined above by B;

[0176] d) reducing the double bond of A′ of compounds of formula

[0177]  wherein R¹-R³, B, X, Y, Z, W, and the dotted line are as definedabove and A′ is a group of formula Ia or Ib as defined above in whichthe dotted line represents a bond, in order to obtain the corresponding2,3-dihydro derivatives, e.g. 2,3-dihydroindole or2,3-dihydrobenzofuran;

[0178] e) reducing the double bond of the tetrahydropyridines of formula

[0179]  wherein R¹-R³, A, B, X, Y, and Z are as previously defined, inorder to obtain the corresponding pipenrdine derivatives;

[0180] f) treating a compound of general formula (I) wherein Y is—CR⁶═CR⁷—, or wherein X and Y together form a group —CR⁴═CRW—, or—CR⁴═CR⁵CR⁶R⁷ with a reducing agent in order to reduce the double bond,thereby obtaining a corresponding reduced ring system;

[0181] g) reductive removal of one or more of the substituents R¹-R³ orR¹²-R¹⁷ in a compound of general formula (I) in which one or more ofthese substituents are selected from chloro, bromo, or iodo;

[0182] h) dialkylating an amine of formula

[0183]  wherein R¹-R³, X, Y, and Z is as defined above with a reagent offormula

[0184]  wherein A and B are as defined above and L is a suitable leavinggroup such as halogen, mesylate, or tosylate;

[0185] i) dialkylating an amine of formula

A—B—NH₂  (XI)

[0186]  wherein A is as defined above with a reagent of formula

[0187]  wherein R¹-R³, X, Y, and Z are as defined above, W′ is N or CH,and L is a suitable leaving group such as halogen, mesylate, ortosylate;

[0188] j) alkylating or acylating the nitrogen atom of the group A″ informula XIII,

[0189]  wherein R¹-R³, B, X, Y, Z, W, and the dotted line are as definedabove, and A″ is a group selected from a group of formula Ia or Ib asdefined above in which either E¹, E², or E³ is NH with alkylating oracylating reagents of formula R⁰-L, wherein L is suitable a leavinggroup such as halogen, mesylate, or tosylate and R⁰ is as defined abovefor R¹¹ but not hydrogen;

[0190] k) cyclization of compounds of formula XIV,

[0191]  wherein R¹-R³, A, B, W, and the dotted line are as defined aboveand X′ is selected from O or S, with dialkylatng reagents of formulaL—Y—L. wherein Y is as defined above and L is a suitable leaving groupas described above;

[0192] 1) cyclization of a compound of formula XVa or XVb,

[0193]  wherein R¹-R³, A, B, X, Y, Z, W, and the dotted line are asdefined above, and L is a suitable leaving groups as defined above or isan N-imidazolyl or pentafluorophenoxy group in order to obtain thecorresponding cyclic oxo-derivatives;

[0194] m) cyclocondensatidn of compounds of formula XVIa or XVIb,

[0195]  wherein R¹-R³, R⁶, A, B, X, Y, Z, WV, and the dotted line are asdefined above in order to obtain the corresponding cyclic hydroxyderivatives, or by successive dehydration to obtain the correspondingunsaturated ring system;

[0196] n) substitution of the hydroxyl group in compounds of formulaXVII,

[0197]  wherein R¹—R³, R⁶—R⁷, A, B, X, Z, W, and the dotted line are asdefined above, with cyanating reagents in order to obtain thecorresponding cyano derivatives;

[0198] o) hydrolysis or reduction of the cyano group of compounds offorrnula XVIII,

[0199] wherein R¹—R³, R⁶—R⁸—, A, B, X, Z, W, and the dotted line are asdefined above, in order to obtain the corresponding carboxylic acidderivatives or the corresponding aminormethyl derivatives;

[0200] p) Oxidation of the hydroxy alkyl chain in compounds of formulaXIX,

[0201]  wherein R¹-R³, R⁶—R⁸, A, B, X, Z, W, and the dotted line are asdefined above, and m=0-4, in order to obtain the correspondingcarboxylic acid derivatives;

[0202] q) hydrolysis and/or reduction of the carboxylic function ofcompounds of formula

[0203]  wherein R¹—R³, R⁶—R⁸, R¹⁸, A, B, X, Z, W, and the dotted lineare as defined above, and m=0-4, in order to get the correspondingcarboxylic acids or alcohols, respectively;

[0204] whereupon the compounds of formula (I) are isolated as the freebase or in the form of a pharmaceutically acceptable salt thereof

[0205] The reduction according to method a) is preferably carned out inan inert organic solvent such as diethyl ether or tetrahydrofuran in thepresence of lithium aluminium hydride at reflux temperature. Startingcompounds of formula (V), in which A is 3-indolyls, are generallyprepared from reagents of formula (VI), 1,3-unsubstituted indoles, andoxalyl chloride according to known literature procedures.

[0206] The alkylation according to method b) is conveniently performedin an inert organic solvent such as a suitably boiling alcohol orketone, preferably in the presence of a base (potassium carbonate ortriethylamine) at reflux temperature. Arylpiperazine derivatives offormula (VI) are conveniently prepared from the corresponding arylamineaccording to the method described by Martin et al, J. Med. Chem., 1989,32, 1052, or the method described by Kruse et al, Rec. Trav. Chim.Pays-Bas, 1988, 107, 303. The starting arylamines are eithercommercially available or are well described in the literature.

[0207] Aryltetrahydropyridine derivatives of formula (VI) are known fromliterature, cf. U.S. Pat. No. 2,891,066; McElvain et al, J. Amer. ChemSoc. 1959, 72, 3134. Conveniently, the corresponding arylbromide islithiated with BuLi followed by addition of 1-benzyl-4-piperidone.Subsequent treatment with acid gives theN-benzy1-ary1tetrahydropyridine. The benzyl group can be removed bycatalytic hydrogenation or by treatment with e.g. ethyl chloroformate togive the corresponding ethyl carbamate followed by acidic or alkalinehydrolysis. The starting arylbromides are either commercially availableor well described in the literature.

[0208] Reagents of formula L-B-A are either commercially available orcan be prepared by literature methods, e.g. from the correspondingcarboxylic acid derivative by reduction to the hydroxy derivatives andconversion of the hydroxy group to the group L by conventional methods.

[0209] The reductive alkylation according to method c) is performed bystandard literature methods. The reaction can be performed in two steps,i.e. coupling of (VI) and the reagent of formula L-B-A by standardmethods via the carboxylic acid chloride or by use of coupling reagentssuch as e.g. dieyclohexyicarbodiimide followed by reduction of the sresulting amide with lithium aluminium hydride. The reaction can also beperformed by a standard one-pot procedure. Carboxylic acids or aldehydesof formula K—B′—A are either commercially available or described in theliterature.

[0210] Reduction of the double bonds according to method d) isconveniently performed by treatment with diborane or a diboraneprecursor such as the trimethylamine or dimethylsulfide complex in aninert solvent such as e.g. tetrahydrofuran or dioxane from 0° C. toreflux temperature followed by acid catalyzed hydrolysis of theintermediate borane derivative. The reduction can alternatively beperformed by treatment with sodium cyanoborohydride in trifluoroaceticacid, by use of magnesium metal, or by catalytic hydrogenation.

[0211] Reduction of the double bonds according to methods e) and f) ismost conveniently perfomed by hydrogenation in an alcohol in thepresence of a noble metal catalyst, such as e.g. platinum or palladium.

[0212] The removal of halogen substituents according to method g) isconveniently performed by catalytic hydrogenation in an alcohol in thepresence of a palladium catalyst or by treatment with ammonium forrnatein an alcohol at elevated temperatures in the presence of a palladiumcatalyst.

[0213] The dialkylation of amines according to methods h) and i) is mostconveniently performed at elevated temperatures in an inert solvent suchas e.g. chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide,or acetonitrile. The reaction might be performed in the presence of basesuch as e.g. potassium carbonate or triethylamine. Starting materialsfor processes h) and i) are commercially available or can be preparedfrom commercially available materials using conventional methods.

[0214] The N-alkylation according to method j) is performed in an inertsolvent, e.g an alcohol or ketone, at elevated temperatures in thepresence of base, e.g. potassium carbonate or triethylamine. at refluxtemperature. Alternatively, a phase-transfer reagent can be used.

[0215] The addition of for example a substituted vicinal dihaloderivative according to method k) by refluxing XIV in a solvent, inertto the selected reaction conditions (e.g. ketones, benzene or alcohol),in the presence of a base, e.g. potassium carbonate, triethylamine orsodium hydroxide in the presence of a phase transfer reagent (Koo, etal. J. Am. Chem. Soc. 1955, 77.5373-5375, Stillings, et al., J. Med.Chem. 1985, 28,1054-1062, Dzvinchuk, et al., Tetrahedron 1986, 386-389).

[0216] Cyclization of keto compounds according to methods l) or m) isperformed, by either base treatment or by employing acidic conditions(See references above in method k, or Thiéry, et al., Tetrahedron 1997,53 (6), 2061-2974).

[0217] Substitution according to method n) can be performed using aLewis acid, e.g., borontrifluoride etherate or trimethylsilyltrifluoromethanesulphonate and an activated nucleophile(trimethylsilylated compounds). (Stillings, et al., J. Med. Chem. 1985,28,1054-1062, Thiéry, et al., Tetrahedron 1997, 53 (6), 2061-2974).

[0218] Reactions according to method o) is performed by use of standardconditions for nitrile hydrolysis and reductions according to method o)is conveniently performed in an inert solvent such as e.g., diethylether or tetrahydrofuran using lithium aluminium hydride or alane.

[0219] Oxidation according to method p) can be performed by usingpotassium peraamanate in a sodium carbonate solution (A. Salimbeni & E.Manghisi. J. Heterocyclic Chem. 1980, 17:489-492).

[0220] Reduction according to method q) can be performed using lithiumaluminium hydride in anhydrous diethyl ether or tetrahydrofuran (Koo, etal., J. Am. Chem. Soc. 1955, 77:5373-5375).

[0221] The following examples will illustrate the invention further.They are, however, not to be construed as limiting.

EXAMPLES

[0222] Melting points were determined on a Büchi B-540 apparatus and areuncorrected. Mass spectra were obtained on a Quattro MS-MS system fromVG Biotech, Fisons Instruments or on a Sciex API 150EX from PerkinElmer. Spectra were obtained at two sets of operating conditions usingelectrospray ionisation: one set to obtain molecular weight information(MH+, 20 eV) and the other set to induce fragmentation patterns (70-100eV). The background was substracted. The relative intensities of theions are obtained from the fragmentation pattern. When no intensity isindicated for the molecular ion (MH+) this ion was only present underthe first set of operating conditions. ¹H NMR spectra were recorded at250 MHz on a Bruker AC 250 or at 500 MHz on a Bruker DRX 500. Deuteratedchloroform (99.8% D) or dimethylsulfoxide (99.9% D) were used assolvents. TMS was used as internal reference standard. Chemical shiftsare expressed as ppm values. The following abbreviations are used formultiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet,qv=quintet, h=heptet, dddouble doublet, dt=double triplet, dq=doublequartet, tt=triplet of triplets, m=multiplet, b=broad. NMR signalscorresponding to acidic protons are to some extent omitted. Content ofwater in crystalline compounds were determined by Karl Fischertitration. Proper elemental analysis for all target compounds wereobtained. Standard work-up procedures refer to extraction with theindicated organic solvent from proper aqueous solutions, drying ofcombined organic extracts (anhydrous MgSO₄ or NaSO₄), filtering, andevaporation of the solvent in vacuo. For column chromatography silicagel of type Kieselgel 60, 40-60 mesh ASTM was used.

Example 1

[0223] 1a, 1-[1,4-Benzodioxan-]5-yl-4-[-(inden-1-yl)-4-butyl]piperazine,oxalate

[0224] A mixture of 4(1-indenyl)butyl methanesulfonate (1.2 g, preparedas described in U.S. Pat. No. 5665725),1-(1,4-benzodioxan-5-yl)piperazine (1.2 g), and potassium carbonate (0.8g) in 3-methyl-2-pentanone (50 mL) was refluxed for 16 h. Cooling,filtration, and removal of solvent in vacuo gave an oil which wasapplied to silica gel flash chromatography (eluent: heptane/methylenechloride/triethylamine 70:26:4). The obtained oil was converted to thetitle oxalate salt (0.7 g) from acetone by addition of oxalic acid. Mp130-31° C. ¹H NMR (DMSO-d₆): 1.60-1.90 (m, 4H); 2.55 (t, 2H); 3.05 (t,2H); 3.15 (s, 8H); 3.35 (s, 8H); 3.35 (s, 2H); 4.15 4.35 (m, 4H); 6.30(s, 1H); 6.50 (t, 1H); 6.60 (s, 1H); 6.75 (t, 1H); 7.20 (t, 1H); 7.25(t,1H); 1H); 7.40 (d, 1H); 7.50 (d, 1H). MS m/z (%):391 (MH+, 79%), 218(37%), 162 (50%), 129 (100%)

[0225] The following compounds were prepared analogously (see U.S. Pat.No. 5,665,725 for preparation of corresponding methanesulfonates):

[0226] 1b, 1-[1,4-Benzodioxan-5-yl)]-4-[1-(indan-1-yl)-1-buten-4-yl)]piperazine, oxalate

[0227] Mp 154-57° C. ¹H NMR (DMSO-d₆): 1.60-1.90 (m, 1H); 2.15-2.35 (m,1H); 2.35-2.50(m, 2H); 2.70-3.00 (m, 2H); 3.05 (t, 2H); 3.20 (s, 8H);3.70 (q, 1H); 4.25 (s, 2H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H);7.00-7.20 (m, 3H); 7.20-7.30(%): 391 (MH+, 62%), 233 (27%), 178 (31%),129 (100%).

[0228] 1c,1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine, oxalate

[0229] Mp 154-55° C. ¹H NMR (DMSO-d₆): 1.25-1.50 (m, 3H), 1.55-1.95 (m,4H); 2.10-2.30(m, 1H); 2.65-2.90 (m, 2H); 2.90-3.10 (m, 3H); 4.10-4.35(m, 4H); 6.50 (d, 1H); 6.75(t, 1H); 7.00-7.15 (m, 2H);7.15-7.25 6.75 (t,1H); 7.00-7.15 (m, 2H); MS m/z (%): 393 (MH+, 100%), 178 (45%), 129(34%).

Example 2

[0230] 2a,1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,oxalate

[0231] A solution of 5-fluorobenzofuran-3-carboxylic acid (56 g) andsaturated etheral solution of hydrochloric gas (300 mL) in methanol (600mL) was stirred for 16 h at room temperature. Further etheral HCl wasadded (300 mL) followed by stirring for 24 h. Concentration in vacuogave a dark crystalline material, methyl5-fluorobenzofuran-3-carboxylate (58 g). Lithium aluminium hydride (15g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmospherefollowed by dropwise addition of a solution of methyl5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). Thetemperature increased to 55° C. during the addition. After stirring for2 h the reaction was quenched successively with water (30 mL), 15% aq.sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran(500 mL) was added and the mixture stirred for 1 h. The mixture wasfiltered and the precipitate extracted with a mixture of methylenechloride (1 L) and ethanol (0.5 L). The combined organic phases wvereconcentrated in vacuo giving an oil which was applied to silica gelflash chromatography (eluent: methylene chloride/25% aq. NH₃ 99: 1). Theresulting yellow oil, 5-fluoroberzo.uran-3-ylmethanol (144 g)crystallised on standing.

[0232] A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylenechloride (250 mL) was treated successively with 5 drops ofdimethylfonnamide and thionyl chloride (28 mL). After stirring for 16 hat room temperature the reaction was concentrated in vacuo giving3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g)

[0233] A suspension of sodium cyanide (10 g) in dimethvlsulfoxide (150mL) was heated to 80° C. followed by quick addition of a solution of3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL).The mixture was kept at 80° C. for ½ h and then poured onto ice.Standard work-up with diethyl ether gave a dark crystalline material,5-fluorobenzofuran-3-ylacetonitrile (8.8 g).

[0234] A solution of 5-fluorobenzofuran-3-ylacetonitrile (8.8 g) inmethanol (350 mL) was treated with a saturated etheral solution ofhydrochloric gas (350 mL) and stirred for 16 h at room temperature. Themixture was concentrated in vacua and standard work-up with diethylether/water gave methyl 5-fluorobenzofiuran-3-ylacetate (9.4 g) as anoil.

[0235] The obtained methyl ester was dissolved in methanol (200 mL) and6 M aq. sodium hydroxide (400 mL) was added followed by stirring for 16at room temperature. Organic solvent was removed in vacuo followed byacidification with 6 M hydrochloric acid. Standard work-up with ethylacetate gave 5-fluorohenzofuran-3-ylacetic acid (9.2 g) as a crystallinematerial.

[0236] A mixture of 5-fluorobenzofiuran-3-ylacetic acid (1.3 g),1-(1,4-benzodioxan-5-yl)piperazine (1.7 g),N,N′-dicyclohexylcarbodiimide (1.6 g), and 4-dimethylaminopyridine (0.1g) in dry tetrahydrofuran (100 mL) was stirred for 72 h at roomtemperature. Filtration, concentration in vacuo and standard work-upwith ethyl acetate/aq. ammonia gave an oil. Purification by flashchromatography on silica gel (eluent: ethylacetate/heptane/triethylamine 82:15:3 gave a yellow oil,1-[1,4-benzodioxan-5-yl]-4-[5-fluorobenzofuran-3-yl)methylcarbonyl]piperazine(0.8 g).

[0237] The oil was dissolved in dry tetrahydrofuiran (30 mL) and addeddropwise to a suspension of lithium aluminium hydnrde (0.38 g) in drytetrahydrofuran (70 mL) under a nitrogen atmosphere at room temperature.After refiux for 3 h the reaction was quenched by successive additionsof water (0.76 mL), 15% aq. sodium hydroxide (0.38 mL), water (1.9 mL).Standard work-up gave an oil which was applied to silica gel flashchromatography (eluents: a) heptane/ ethyl acetateltnrethylamine55:43:2, b) ethyl acetate/heptane/triethylamine 70:26:4). The resultingoil (0.7 g) was dissolved in ethyl acetate and addition of oxalic acid(0.17 g) and filtration gave the title oxalate as white colourlesscrystals. Mp 210-17° C. ¹H NMR (DMSO-d₆): 3.00 (t, 2H); 3.20 (s, 8H);4.00 (t, 2H); 4.25 (d, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.25 (t, 1H);7.15 (t, 1H); 7.50-7.70 (m, 2H; 8.00 (s, 1H). MS mn/z (%): 383 (MH+,8%),233 (60%), 218 (22%), 190 (21%), 70 (100%)

[0238] The following compound was prepared analogously:

[0239] 2b,1[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyl]piperazine,oxalate

[0240] Mp 111-13 °C. ¹H NMR (DMSO-d₆): 2.95-3.35 (m, 12H); 4.25 (dd,4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.15 (d, 1H); 7.55 (s,1H); 7.85 (d, 1H).MS m/z (%): 399 (M, 399 (MH+, 22%), 218 (100%), 162(45%). The starting 6-chloroindazol-3-yl acetic acid was preparedaccording to J. Med. Chem. 35 (1992) 2155.

Example 3

[0241] 3a,1-[Benzofuran-7-yl]-4-[2(5-fluorobenzofuran-3-yl)ethyl]piprazine,fumarate

[0242] A solution of 5-fluorobenzofuran-3-ylacetic acid (4.6 g, preparedas described in Example 2) in dry tetrahydrofuran (200 mL) was addeddropwise to a suspension of lithium aluminium hydride (4.5 g) in drytetrahydrofuran (150 mL) at room temperature. After reflux for 2 h thereaction was quenched by successive additions of water (9.2 mL), 15% aq.sodium hydroxide (4.6 mL), water (23 mL). Filtration and removal ofsolvent in vacuo gave an oil, 2-(5-fluorobenzofuran-3-yl)ethanol (4.3g).

[0243] A solution of 2-(5-fluorobenzofuran-3-yl)ethanol (5.2 g) andtetrabromomethane (11.6 g) in acetonitrile (175 mL) was treated withtnrphenylphosphine (8.3 g) at 0° C. After stirring for 15 min, themixture was concentrated in vacuo an the resulting oil was applied to asilica gel flash column (eluent: heptaneiethyl acetate 65:35) resultingin an oil, 3(2-bromoethyl)-5-fluorobenzofuran (7.4 g).

[0244] A mixture of 3-(2-bromoethyl)-5-fluorobenzofiran (1.4 g),1-(benzofuran-7-yl)piperazine (1.0 g), potassium carbonate (1.5 g), andpotassium iodide (0.1 g) in 3-methyl-2-pentanone (100 mL) was refluxedfor 16 h. Addition of water (100 mL) followed by standard work-up gavean oil which was applied to silica gel flash chromatography (eluent:heptane/ethyl acetate/triethylamine 80:15:5). The resulting oil wasdissolved in ethanol and addition of fumaric acid gave the titlefumarate as a colourless crystalline material (0.9 g). Mp 177-79° C. ¹HNMR (DMSO-d₆): 2.70-2.80 (m, 6H); 2.90 (t, 2H); 3.25-3.35 (m, 4H); 6.60(s, 2H); 6.75 (d, 1H); 6.90 (d, 1H); 7.10-7.25 (m, 3H); 7.55 (dd, 1H);7.60 (dd, 1H); 7.90-8.00 m, 2H). MS rn/z (%): 365 (MH+, 5%), 215 (90%),172 (22%), 163 (12%), 70 (100%).

[0245] The following compounds were prepared analogously:

[0246] 3b,1-1,4[-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[2]isoxazol-3-yl)-1-propyl]fumarate

[0247] Mp 187-89° C. ¹H NMR (DMSO-d₆): 2.00 (qv, 2H); 2.55 (t, 2H);2.55-2.70 (m, 4H); 2.85-3.00 (m, 4H); 3.05 (t, 2H); 4.15-4.30 (m, 4H);6.45 (dd, 1H); 6.50 (dd, 1H); 6.6 6.75 (t, 1H); 7.25 (dt, 1H); 7.70 (dd,1H); 8.00 (dd, 1H). MS m/z (%): 398 (MH+, 9%), 221 (7%), 177 (100%), 150(9%). The starting 3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl chloridewas prepared according to Drug Design Discov.,1992, 8, 225.

[0248] 3c,1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,oxalate

[0249] Mp 204-6° C. ¹H NMR (DMSO-d₆): 2.65 (s, 3H); 3.10-3.40 (m, 12H);4.25 (dd, 4H);6.50 (d, 1H) (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.00 (d,1H); 7.20 (t, 3H); 7.40 (d, 1H); 7.80 (s, 1H). MS m/z (%): 379 (MH+,20%), 233 (75%), 218 (100%), 190 (43%), 162 (85%).

[0250]3d,1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,oxalate

[0251] Mp 206-8° C. ¹H NMR (DMSO-d₆): 3.05 (t, 2H); 3.10-3.40 (m, 10H),4.10-4.35 (m, 4H) 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H): 7.35 (dd,1H): 7.65 (d, 1H); 7.85 (d, 1H); 8.00 (s, 1H). MS m/z (%): 399 (MH+,45%). 293 (100%), 218 (77%), 190 (40%), 162 (48%).

[0252] 3e,1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,oxalate

[0253] Mp 174-76° C. ¹H NMR (DMSO-d₆): 3.00 (t, 2H); 3.10-3.40 (m, 10H);4.10-4.35 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.10 (dd,1H); 7.35 (s, 1H); 7.60 (d, 1H);7.80 (s, 1H). MS m/z (%): 379 (MH+,22%), 2,3 (100%), 218 (61%), 162 (59%).

[0254] 3f, 1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine, oxalate

[0255] Mp 206-8° C. ¹H NMR (DMSO-d₆): 3.05 (t, 1H), 3.10-3.40 (m, 10H);4.10-4.35 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.20-7.40(m, 2H); 7.55 (dd, 1H); 7.75 (dd, 1H); 7.90 (s, 1H). MS m/z (%): 365(MH+, 41%), 233 (100%), 218 (96%), 190 (61%), 162 (87%).

[0256] 3g,1-[2-(5-Chlorobenzofuran-3-yl)ethyl]4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine,oxalate

[0257] Mp 187-202° C. ¹H NMR (DMSO-d₆): 2.75 (s, 1H); 3.15 (t, 2H); 3.20(t, 2H); 3.25-3.45 (m, 4H); 3.85 (s, 2H); 4.60 (t, 2H); 6.35 (s, 1H);6.85 (t, 1H); 7.10 (d, 1H) 7.20 ( d, 1H); 7.35 (d, 1H); 7.60 (d, 1H);7.85 (s, 1H); 8.00 (s, 1H). MS m/z (%): 380 (MH+, 14%), 179 (90%),144(59%), 115 (100%).

[0258] 3h,4-[Benzofuran-7-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,oxalate

[0259] Mp 201-11° C. ¹H NMR(DMSO-d₆): 2.90 (s, 2H); 3.15 (t, 2H); 3.35(t, 2H); 3.40-3.50 (m 2H); 3.95 (s, 2H); 6.65 (s, 1H); 7.00 (s, 1H);7.20 (dt, 1H); 7.30 (t, 1H); 7.35 (d, 1H) 7.55-7.65 (m, 3); 8.00 (s,1H); 8.05 (s, 1H). MS m/z (%): 362 (MH+, 18%), 192 (22%), 163 (83%), 135(92%), 115 (00%).

[0260] 3i,1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethy]piperazine,oxalate

[0261] Mp 190-92° C. ¹H NMR (DMSO-d₆): 2.95-3.35 (m, 12H); 4.15-4.30 (m,4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.35 (t, 1H); 7.45 (d,1H); 7.75 (d. 1H); 8.00 (s, 1H). MS m/z (%): 399 (MH+), 233 (100%), 218(49%), 162 (49%), 116 (69%).

EXAMPLE 4

[0262]4a,1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,oxalate

[0263] Malonic acid diethyl ester (8.5 g) was dissolved indimethylformamide (75 mL) followed by addition of potassiumtert-butoxide (5.9 g). After stirring for 15 min at room temperature, asolution of 3-chloromethyl-7-chloro4-methylbenzofiaran (3.8 g, preparedanalogously to the 5-fluoro analogue as described in Example 2) indimethylformamide (25 mL) was added dropwise. After stirring for 2 hoursthe reaction mixture was poured onto ice-water. Standard work-up withacetyl acetate gave a yellow oil (10 g) of diethyl2-(7-chloro-4-methylbenzofuran-3-yl)malonate, sufficiently pure forfurther synthesis. A portion of this product (6.0 g) was dissolved inacetone (50 mL) and stirred for 5 min followed by addition of water (50mL) and conc. hydrochloric acid (50 mL). After reflux for 16 hours, thereaction mixture was cooled to room temperature and extracted with ethylacetate. Standard washing procedure with ammonia and 2 M hydrochloricacid, drying of the organic phase over magnesium sulfate, filtration andremoval of solvent in vacuo gave3-(7-chloro4-methylbenzofiuran-3-yl)propionic acid (2.5 g) as acolorless solid. Treatment of this solid (2.5 g) with thionyl chloride(12 g) in methylenle chloride and 1 drop of dimethylfornamide at refluxfor 3 hours followed by concentration of the reaction mixture in vacuogave 3-(7-chloro-4-methylbenzofuran-3-yl)propionyl chloride (2.7 g) as abrown oil.

[0264] The oil was dissolved in trichloroethane (25 mL) and addeddropwise to a mixture of 1-(benzodioxane-5-yl)piperazine (1.9 g) andtriethylamine (10 mL) in trichloroethane (75 mL) over 15 min at roomtemperature. After reflux for 16 hours, the reaction mixture wasconcentrated in vacuo and the resulting oil applied to silica gel flashchromatography (eluent: ethyl acetate/heptane/tnrethylamine 15:4:1)giving1-(benzodioxane-5-yl)-4-[2-(7-chloro-4-methylbenzofuran-3-yl)ethylcarbonyi]piperazine(2.1 g) as a yellow oil. The product was dissolved in drytetrahydrofuran (25 mL) and added dropwise to a suspension of lithiumaluminium hydnrde (1.5 g) in dry tetrahydrofuiran (75 mL). The mixturewas stirred for 45 min at room temperature. The mixture was quenched bysuccessive addition of water (1 mL), 15% sodium hydroxide (0.5 mL), andwater (1.5 mL). After stirring for 2 hours, the mixture was filtered andconcentrated in vacuo. The resulting oil was applied to flashchromatography (eluent:ethyl acetate/leptane 1:1) giving the titlecompound which was crystallised as the filmarate salt (0.7 g) fromacetone.

[0265] Mp 178-81° C. ¹H NMR (DMSO-d₆): 2.00 (qv, 2H); 2.60 (s, 3H); 2.85(t, 2H); 3.10 (t, 2H); 3.15 (broad s, 8H); 4.15-4.35 (m, 4H); 6.50 (d,1H); 6.55 (d, 1H); 6.75 (t 1H); 7.05 (d, 1H); 7.25 (d, 1H); 7.90 (s,1H).

[0266] MS m/z (%): 427 (MH+, 100%), 218 (43%), 178 (71%), 122 (80%).

[0267] The following compounds were prepared analogously:

[0268] 4b, 1-[1,4-Benzodoxan-5-yl]-4-[3-(7-chloro-benzofuran-3-yl)-1-propyl]piperazine, fumarate

[0269]¹H NMR (DMSO-d₆): 1.85 (qv, 2H); 2.40 (t, 2H); 2.55 (broad s, 4H);2.70 (t, 2H); 3.00 (broad s, 4H); 4.10-4.30 (m, 4H); 6.45 (d, 1H); 6.50(d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 7.25 (t, 1H); 7.40 (d, 1H); 7.65(d, 1H);. 7.90 (s, 1H).

[0270] MS m/z (%): 413 (41%), 218 (10%), 178 (100%), 122 (62%).

[0271] 4c1-[3-(7-Chlorobenzofuran-3-yl)-1-propyl]-4-[8-cyano-1,4-benzodioxan-5-yl]piperazine,fumarate

[0272]¹H NMR (DMSO-d₆): 1.85 (qv, 2H); 2.40 (t, 2H); 2.55 (broad s, 4H);2.70 (t, 2H); 3.10 (broad s, 4H); 4.25-4.35 (m, 2H); 4.35-4.45 (m, 2H);6.55 (d, 1H); 6.60 (s, 1H); 7,20 (d, 1H); 7.30 (t, 1H); 7.40 (d, 1H);7.65 (d, 1H); 7.95 (s, 1H).

[0273] MS m/z (%): 438 (MH+, 73%), 243 (100%), 203 (68%), 165 (84%).

EXAMPLE 5

[0274] 5a,1-[1,4-Beizzodioxan-5-yl]-4-[3-(4-methlbenzofuran-3-yl)-1-propyl]piperazine,oxalate

[0275] A mixture of 4a (0.6 g), palladium on charcoal (5%, 0.6 g), 2 Msodium hydroxide solution (2 mL) and methanol (50 mL) was hydrogenatedin a Parr apparatus at 3 atm of hydrogen pressure for 1.5 hours.Filtration, addition of ethyl acetate, washing with water, and removalof solvents iin vacuo gave the title compound as a yellow oil which wascrystallised as the fumarate salt (0.4 g) from acetone.

[0276] Mp 212-14° C. ¹H NMR (DMSO-d₆): 2.05 (qv, 2H); 2.55 (s, 3H); 2.85(t, 2H); 3.10 (t, 2H); 3.20 (broad s. 2H); 4.10-4.30 (m, 4H); 6.50 (d,1H); 6.55 (d, 1H); 6.75 (t, 1H); 700 (d, 1H); 7.20 (t, 1H); 7.85 (d,1H); 7.75 (s, 1H).

[0277] MS m/z (%): 393 (MH+, 32%), 218 (45%), 178 (60%), 189 (100%).

[0278] Pharmacological Testing

[0279] The affinity of the compounds of the invention to 5-HT_(1A)receptors was determined by measuring the inhibition of binding of aradioactive ligand at 5-HT_(1A) receptors as described in the followingtest:

[0280] Inhibition of ³H-5-CT Binding to Human 5-HT_(1A) Receptors

[0281] By this method the inhibition by drugs of the binding of the5-HT_(1A) agonist ³H-5-carboxamido tryptamine (³H-5-CT).to cloned human5-HT_(1A) receptors stably expressed in transfected HeLa cells (HA7)(Fargin, A. et al, J. Biol. Chem., 1989, 264, 14848) is determined invitro. The assay was performed as a modification of the method describedby Harrington, M. A. et al, J. Pharmacol. Exp. Ther., 1994, 268, 1098.Human 5-HT_(1A) receptors (40 μg of cell homogenate) were incubated for15 minutes at 37° C. in 50 mM Tris buffer at pH 7.7 in the presence of³H-5-CT. Non-specific binding was determined by including 10 μM ofmetergoline. The reaction was terminated by rapid filtration throughUnifilter GF/B filters on a Tomtec Cell Harvester. Filters were countedin a Packard Top Counter. The results obtained are presented in table 1:TABLE 1 Compound Inhibition of ³H-5-CT binding No. IC₅₀ (nM) 1a 1.7 1b6.1 1c 2.5 2a 14 2b 9.3 3a 29 3b 7.5 3c 19 3d 18 3e 8.8 3f 8.3 3g 24 3h11 3i 2.1 5a 2.9 Pindolol* 100

[0282] The compounds of the invention have also been tested for theireffect on re-uptake of serotonin in the following test:

[0283] Inhibition of ³H-5-HT Uptake Into Rat Brain Synaptosomes

[0284] Using this method, the ability of drugs to inhibit theaccumulation of ³H-5-HT into whole rat brain synaptosomes is determinedin vitro. The assay was performed as described by Hyttel, J.,Psychopharmacology 1978, 60, 13. The results obtained are presented intable 2: TABLE 2 Compound Inhibition of serotonin reuptake No. IC₅₀ (nM)1a 61 1c 130 2a 0.69 2b 160 3a 170 3b 240 3c 11 3d 34 3e 58 3f 12 3g 1603h 43 3i 1.5 4a 32 5a 15 Paroxetine* 0.29

[0285] The 5-HT_(1A) antagonistic activity of some of the compounds ofthe invention has been estimated in vitro at cloned ⁵-HT_(1A) receptorsstably expressed intransfected HeLa cells (HA7). In this test 5-HT_(1A)antagonistic activity is estimated by measuring the ability of thecompounds to antagonize the 5-HT induced inhibition of forskolin inducedcAMP accumulation. The assay was performed as a modification of themethod described by Pauwels, P. J. et al, Biochem. Pharmacol. 1993, 45,375. The results obtained are presented in table 3: TABLE 3 CompoundAntagonism of Inhibition of forskolin induced No. cAMP accumulation IC₅₀(nM) 1a  170 2a  100 3b  74 3c 2300 3d  550 3e 1400 3f  290 3i 1500 4a 260 5a  390 Pindolol*  270

[0286] Some of the compounds of the invention have also been tested fortheir in vivo effect on 5-HT_(1A) receptors in the assay described bySanchez. C. Et al., Eur. J. Pharmacol., 1996, 315. pp 245. In this test,antagonistic effects of test compounds are determined by measuring theability of the test compounds to inhibit 5-MeO-DMT induced 5-HTsyndrome.

[0287] The compounds of the present invention possess valuable activityas serotonin re-uptake inhibitors and have antagonistic effect at5-HT_(1A) receptors. The compounds of the invention are thereforeconsidered useful for the treatment of diseases and disorders responsiveto the inhibition of serotonin re-uptake and antagonistic activity at5-HT_(1A) receptors. Diseases responsive to theinhibition of serotoninre-uptake are well known in the art and include affective disorders,such as depression, psychosis, anxiety disorders including generalanxiety disorder, panic disorder, obsessive compulsive disorder, etc.

[0288] As explained above, the antagonistic activity at 5-HT_(1A)receptors of the compounds of the invention will counteract the negativefeed back mechanism induced by the inhibition of serotonin reuptake andis thereby expected to improve the effect of the serotonin reuptakeinhibiting activity of the compounds of the invention.

[0289] The compounds as claimed herein are therefore considered to beparticularly useful as fast onset of action medicaments for thetreatment of depression. The compounds may also be useful for thetreatment of depressions which are non-responsive to currently availableSSRIs.

[0290] Pharmaceutical Formulation

[0291] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art. For example: Tablets may be preparedby mixing the active ingredient with ordinary adjuvants and/or diluentsand subsequently compressing the mixture in a conventional tablettingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvants or additives usually used for such purposessuch as colourings, flavourings, preservatives etc. may be used providedthat they are compatible with the active ingredients.

[0292] Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilization of the solution and filling in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

[0293] The pharmaceutical compositions of this invention or those whichare manufactured in accordance with this invention may be administeredby any suitable route, for example orally in the form of tablets,capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and any pharmaceutically acceptablecarriers, diluents, excipients, or other additives normally used in theart may be used.

[0294] Conveniently, the compounds of the invention are administered inunit dosage form containing said compounds in an amount of about 0.01 to1000 mg. The total daily dose is usually in the range of about 0.05-500mg, and most preferably about 0.1 to 50 mg of the active compound of theinvention.

1. A pipenrdine, tetrahydropyridine or piperazine derivative having theformula:

any of its enantiomers or any mixture thereof, or an acid addition saltthereof, wherein B is C₁₋₁₀-alkylene, C₂₋₁₀-alkenylene orC₂₋₁₀-alkynylene; X is —O—, —S—, or —CR⁴R⁵—; and Y is —CR⁶R⁷—,—CR⁶R⁷—CR⁸R⁹—, or —CR⁶—CR⁷—; or X and Y together form a group —CR⁴═CR⁵—,or —CR⁴═CR⁵—CR⁶R⁷—; Z is —O—, or —S—; W is N, C, or CH, and the dottedline is an optional bond; R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are eachindependently selected from hydrogen, halogen, trifluoromethyl,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl,C₃₋₇-cycloalkyl-C₁₋₆alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, phenylamino orphenyl-C₁₋₆-alkylamino wherein the phenyl group may be substituted,acylamino, hydroxy, —SH, cyano, nitro, —COOR¹⁸, —SO₂—R¹⁹ and C₁₋₆-alkylsubstituted with a substituent selected from halogen, C₁₋₆-alkoxy,C₁₋₆alkylthio, amino, C₁₋₆alkylamino, C₁₋₆-dialkylamino, acylamino,hydroxy, —SH, cyano, nitro, —COOR¹⁸ and —SO₂—R¹⁹; R¹⁸ is hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, phenyl or phenyl-C₁₋₆-alkylwherein the phenyl groups may be substituted, amino, C₁₋₆-alkylamino orC₁₋₆-dialkylamino, and R¹⁹ is C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, phenyl or phenyl-C₁₋₆-alkyl wherein the phenyl groupsmay be substituted; A is a bicyclic ring selected from

wherein E¹, E² and E³ are selected from O, S, N, NR¹¹, C, CR¹² andCHR¹³, and the dotted line indicates an optional bond, provided that E²and E¹ and/or E³ may not simultaneously be O, or S; R¹, R², R³, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are each independently selected fromhydrogen, halogen, trifluoromethy, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkoxy,hydroxy, formyl, acyl, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,acylamino, C₁₋₆-alkoxycarbonylamino, aminocarbonylamino,C₁₋₆-alkylaminocarbonylamino, C₁₋₆-dialkylaminocarbonylamino, nitro,cyano and —SO₂-R¹⁹, wherein R¹⁹ is C₁₋₆-alkyl, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, phenyl, or phenyl-C₁₋₆-alkyl wherein the phenylgroups may be substituted; R¹¹ is selected from hydrogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, C₃₋₇-cycloalkyl-C₁₋₆-alkyl,phenyl or phenyl-C₁₋₆-alkyl wherein the phenyl group may be substituted,acyl, formyl and —SO₂—R¹⁹, wherein R¹⁹ is C₁₋₆-alkyl, amino,C₁₋₆alkylamino, C₁₋₆-dialkylamino, phenyl or phenyl-C₁₋₆-alkyl whereinthe phenyl groups may be substituted; provided that at least one ofR⁴—R⁹ is different from hydrogen when A is a group of formula


2. A compound according to claim 1 wherein A is selected from the groupsof formula (Ic), (Id) and (Ie)

wherein E¹, E², E³, and R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as defined in claim 1and E⁵ is N, C or CR¹².
 3. A compound according to claims 1 to 2 whereinthe bicyclic ring A is selected from the group (If) to (Iq)

which is attached to the remainder of the compound of formula (I) via acarbon atom or a nitrogen atom in any of the two rings and wherein thedotted line is an optional bond, E⁶ is O or S, and wherein any of thecarbon atoms in the ring may be substituted with any of the substituentsdefined for R¹²-R¹⁷ above, and wherein the nitrogen atoms in the ringmay be substituted with any of the substituents defined above for R¹¹.4. A compound according to claim 3 wherein A is a group of formula (Ih),(Ij) or (Iq).
 5. A compound according to claim 4 wherein A is a group offormula (Ih) wherein E⁶ is O.
 6. A compound according to claims 4 to 5wherein A is attached to the remainder of the derivative of formula (I)via position 3 in the five-membered ring.
 7. A compound according toclaim 3 wherein A is a group of formula (If).
 8. A compound according toany of claims 1-7 wherein B is C₁₋₆-alkylene, C₂₋₆-alkenylene, orC₂₋₆-alkynylene; X is —O—, or —S—; and Y is —CR⁶R⁷—, —CR⁶R⁷—CR⁸R⁹—, or—CR⁶═CR⁷—; and Z is —O—, or —S—; W is N, C, or CH; R⁶, R⁷, R⁸ and R⁹ areeach independently selected from hydrogen, halogen, trifluoromethyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, amino, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, phenylamino or phenyl-C₁₋₆-alkylamino wherein thephenyl group may be substituted, hydroxy, cyano, nitro, —COOR¹⁸,—SO₂—R¹⁹ and C₁₋₆-alkyl substituted with halogen, C₁₋₆-alkoxy,C₁₋₆-alkylthio, amino, C₁₋₆-alkylamino, C₁₋₆-dialkylamino, acylamino,hydroxy, cyano, nitro, —COOR¹⁸ or —SO₂—R¹⁹; R¹⁸ is hydrogen, C₁₋₆-alkyl,amino, C₁₋₆-alkylamino or C₁₋₆-dialkylamino; R¹⁹ is C₁₋₆-alkyl, amino,C₁₋₆-alkylamino or C₁₋₆-dialkylamino; R¹, R², R³, R¹², R¹³, R¹⁴, R¹⁵,R¹⁶ and R¹⁷ are each independently selected from hydrogen, halogen,trifluoromethyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy, amino,C₁₋₆-alkylamino, C₁₋₆-dialkylamino, nitro and cyano; and R¹¹ is selectedfrom hydrogen, C₁₋₆-alkyl, phenyl or phenyl-C₁₋₆-alkyl wherein thephenyl group may be substituted, acyl, formyl and —SO₂—R¹⁹, wherein R¹⁹is C₁₋₆-alkyl, amino, C₁₋₆-alkylamino or C₁₋₆-dialkylamino.
 9. Acompound according to claim 1 which is selected from1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten-4-yl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(6chloroindazol-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine,4-[Benzofaran-7-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,1-[1,4-Benzodioxan-5-yl]-4-[2-(7chlorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)-1-proyl]piperazine,1-[8-Cyano-1,4-benzodioxan-5-yl]-4-[3-(7-chlorobenzofuran-3-yl)propyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(7chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine1-[1,4-Benzodioxan-5-yl]-4-[2-(6-bromobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(4-chlorobenzofuran-3-yl)-1-propyl]piperazine1-[1,4-Benzodioxan-5-yl]-4-[4-(4-methylbenzofuran-3-yl)-1-butyl]piperazine1-[1,4-Benzodioxan-5-yl]-4-[4-(4-chlorobenzofuran-3-yl)-1-butyl]piperazine1-[1,4-Benzodioxan-5-yl]-4-[4-(7-chlorobenzofuran-3-yl)-1-butyl]piperazine4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,4-[1,4-Benzodioxan-5-yl]-1-[2-(5-fluorobenzofuran-3-yl)ethyl]piperidine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperazine,1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperazine,1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4benzodioxan-5-yl]tetrahydropyridine,4-[6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]tetrahydropyridine,1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-hydroxymethyl-1,4-benzodioxan-5-yl]piperidine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-cyano-1,4-benzodioxan-5-yl]piperidine4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-trifluoromethyl-1,4-benzodioxan-5-yl]piperidine,4-[2-(6-Chloro-1H-indol-3-yl]-1-[2-(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]piperidine,1-[2-Carbamoyl-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylcarbamoyl)-1,4-benzodioxan-5-yl]piperidine,1-[2-Amino-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,1-[2-Acetamido-1,4-benzodioxan-5-yl]-4-[2-(6-Chloro-1H-indol-3-yl)ethyl]piperidine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2-(N,N-dimethylamino)-1,4-benzodioxan-5-yl]piperidine,1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperazine,1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperazine,1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]tetrahydropyridine,1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]tetrahydropyridine,b1-[2,2-Bis(hydroxymethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,4-[2-(6-Chloro-1H-indol-3-yl)ethyl]-1-[2,2-dicyano-1,4-benzodioxan-5-yl]piperidine,1-[2,2-Bis(trifluoromethyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,1-[2,2-Bis(ethyl-oxo-carbonyl)-1,4-benzodioxan-5-yl]-4-[2-(6-chloro-1H-indol-3-yl)ethyl]piperidine,or a pharmaceutically acceptable acid addition salt thereof.
 10. Acompound according to claim 1 which is selected from1-[1,4-Benzodioxan-5-yl]-4-[1-(inden-1-yl)-4-butyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-1-buten-4-yl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[1-(indan-1-yl)-4-butyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(6-fluorobenzo[1,2]isoxazol-3-yl)-1-propyl]piperazine,1-[Benzofuran-7-yl]-4-[2-(5-fluorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(6-chloroindazol-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(4-methylbenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(5-chlorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(6-methylbenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(benzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[2-(7-chlorobenzofuran-3-yl)ethyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(7-chloro-4-methylbenzofuran-3-yl)-1-propyl]piperazine,1-[1,4-Benzodioxan-5-yl]-4-[3-(4-methylbenzofuran-3-yl)-1-propyl]piperazine,1-[2-(5-Chlorobenzofuran-3-yl)ethyl]-4-[2,3-dihydrobenzofuran-7-yl]-1,2,3,6-tetrahydropyridine,and4-[Benzofuran-7-yl-]1-[2-(5-fluorobenzofuran-3-yl)ethyl]-1,2,3,6-tetrahydropyridine,or a pharmaceutically acceptable acid addition salt thereof.
 11. Apharmaceutical composition containing a compound of formula (I) or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable carrier or diluent.
 12. The use of acompound of formula (I) or a pharmaceutically acceptable acid additionsalt thereof for the preparation of a medicament for the treatment of adisorder or disease responsive to the inhibition of serotonin reuptakeand antagonism of 5-HT_(1A) receptors.
 13. The use of a compound orformula I or a pharmaceutically acceptable acid addition salt thereoffor the preparation of a medicament for the treatment of affectivedisorders, such as depression, psychosis, anxiety disorders includinggeneral anxiety disorder, panic disorder, obsessive compulsive disorder,and eating disorders.
 14. A method of treating affective disorders, suchas depression, psychosis, anxiety disorders including general anxietydisorder, panic disorder, obsessive compulsive disorder, and eatingdisorders comprising administering a compound of formula (I) or apharmaceutically acceptable acid addition salt thereof.